Recent Advances in Understanding the Micro- and Nanoscale Phenomena of Amorphous Solid Dispersions.

Many pharmaceutical drugs in the marketplace and discovery pipeline suffer from poor aqueous solubility, thereby limiting their effectiveness for oral delivery. The use of an amorphous solid dispersion (ASD), a mixture of an active pharmaceutical ingredient and a polymer excipient, greatly enhances the aqueous dissolution performance of a drug without the need for chemical modification. Although this method is versatile and scalable, deficient understanding of the interactions between drugs and polymers inhibits ASD rational design. This current Review details recent progress in understanding the mechanisms that control ASD performance. In the solid-state, the use of high-resolution theoretical, computational, and experimental tools resolved the influence of drug/polymer phase behavior and dynamics on stability during storage. During dissolution in aqueous media, novel characterization methods revealed that ASDs can form complex nanostructures, which maintain and improve supersaturation of the drug. The studies discussed here illustrate that nanoscale phenomena, which have been directly observed and quantified, strongly affect the stability and bioavailability of ASD systems, and provide a promising direction for optimizing drug/polymer formulations.

Enhanced Performance of Blended Polymer Excipients in Delivering a Hydrophobic Drug through the Synergistic Action of Micelles and HPMCAS.

Blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and dodecyl (C12)-tailed poly(N-isopropylacrylamide) (PNIPAm) were systematically explored as a model system to dispense the active ingredient phenytoin by rapid dissolution, followed by the suppression of drug crystallization for an extended period. Dynamic and static light scattering revealed that C12-PNIPAm polymers, synthesized by reversible addition-fragmentation chain-transfer polymerization, self-assembled into micelles with dodecyl cores in phosphate-buffered saline (PBS, pH 6.5). A synergistic effect on drug supersaturation was documented during in vitro dissolution tests by varying the blending ratio, with HPMACS primarily aiding in rapid dissolution and PNIPAm maintaining supersaturation. Polarized light and cryogenic transmission electron microscopy experiments revealed that C12-PNIPAm micelles maintain drug supersaturation by inhibiting both crystal nucleation and growth. Cross-peaks between the phenyl group of phenytoin and the isopropyl group of C12-PNIPAm in 2D 1H nuclear Overhauser effect (NOESY) spectra confirmed the existence of drug-polymer intermolecular interactions in solution. Phenytoin and polymer diffusion coefficients, measured by diffusion-ordered NMR spectroscopy (DOSY), demonstrated that the drug-polymer association constant increased with increasing local density of the corona chains, coincident with a reduction in C12-PNIPAm molecular weight. These findings demonstrate a new strategy for exploiting the versatility of polymer blends through the use of self-assembled micelles in the design of advanced excipients.

Nanoscale Concentration Quantification of Pharmaceutical Actives in Amorphous Polymer Matrices by Electron Energy-Loss Spectroscopy.

We demonstrated the use of electron energy-loss spectroscopy (EELS) to evaluate the composition of phenytoin:hydroxypropyl methylcellulose acetate succinate (HPMCAS) spin-coated solid dispersions (SDs). To overcome the inability of bright-field and high-angle annular dark-field TEM imaging to distinguish between glassy drug and polymer, we used the π-π* transition peak in the EELS spectrum to detect phenytoin within the HPMCAS matrix of the SD. The concentration of phenytoin within SDs of 10, 25, and 50 wt % drug loading was quantified by a multiple least-squares analysis. Evaluating the concentration of 50 different regions in each SD, we determined that phenytoin and HPMCAS are intimately mixed at a length scale of 200 nm, even for drug loadings up to 50 wt %. At length scales below 100 nm, the variance of the measured phenytoin concentration increases; we speculate that this increase is due to statistical fluctuations in local concentration and chemical changes induced by electron irradiation. We also performed EELS analysis of an annealed 25 wt % phenytoin SD and showed that the technique can resolve concentration differences between regions that are less than 50 nm apart. Our findings indicate that EELS is a useful tool for quantifying, with high accuracy and sub-100 nm spatial resolution, the composition of many pharmaceutical and soft matter systems.

Detection of pharmaceutical drug crystallites in solid dispersions by transmission electron microscopy.

We explored the use of transmission electron microscopy (TEM) to evaluate the crystallinity of griseofulvin (GF)/hydroxypropyl methylcellulose acetate succinate (HPMCAS) solid dispersions. TEM, which provides both real-space images and electron diffraction patterns, was used to unambiguously identify GF crystals in spray dried GF. Using TEM, we were also able to detect GF crystals in a physical mixture of spray dried GF particles and spray dried HPMCAS particles with an overall crystallinity of ∼3 vol %, below the practical lower limit of detection for laboratory-scale wide-angle X-ray scattering (WAXS). Using TEM and WAXS, we did not find crystals in GF/HPMCAS solid dispersions with GF loadings of 5, 10, and 50 wt %. However, we detected GF crystals in annealed 5 wt % GF solid dispersion using TEM, whereas we did not detect crystals using in situ WAXS and modulated differential scanning calorimetry, thereby establishing the superior crystal detection sensitivity of TEM. We also performed TEM analysis of the in situ growth of GF crystals in a TEM sample of 50 wt % GF solid dispersion. Based on this study, TEM has significant potential for characterizing even small degrees of crystallinity in solid dispersions.